The purpose of this grant proposal is to determine how and in what manner paternal morphine exposure affects their progeny. In several recent studies, we observed a number of behavioral and endocrinological abnormalities in the male and female offspring produced by breeding male rats, who had been exposed to morphine during adolescence, with, drug-naive females. These abnormalities were evident even though breeding occurred following an extended drug-free period after the acute and chronic effects of morphine on endocrine and developmental parameters had dissipated. The studies in this grant proposal will continue our analysis of the effects of paternal exposure to morphine on their progeny and address issues important for understanding the parameters involved and the underlying mechanisms. The critical question of whether the offspring show an abnormal sensitivity or tolerance to the acute effects of morphine and its dependence producing properties, in addition to endocrine and behavioral abnormalities, will also be addressed. Our specific aims are: First, to further characterize the behavioral, cognitive and physiological deficits observed in male and female offspring of morphine-exposed fathers. Second, to determine whether the acute sensitivity to morphine and the development of tolerance and physical dependence are altered in the offspring of morphine-exposed fathers. Third, to determine whether the age of initial paternal exposure to morphine is a critical factor in the deficits observed in their offspring. Fourth, to determine whether the deficits observed in the offspring of morphine-exposed male rats persist in subsequent generations, ie, are the deficits heritable? Fifth, to begin to examine the mechanisms underlying the adverse effects of paternal opiate exposure on their offspring. The proposed studies could have far-reaching clinical significance. Although there is a clear recognition of the deleterious effects of maternal drug abuse on the development of their offspring, there has been little concern about another variable of potentially equal importance: the role of drug-abuse in the father on their offspring. Our success in the generation of an animal model to examine the paternal effects of morphine abuse could thus be instrumental in focussing on a heretofore unrecognized factor leading to birth defects and possibly the transmission of susceptibility to drug abuse.